Cyclic regimens using cyclocarbamate and cyclic amide derivatives

Abstract

This invention relates to cyclic combination therapies and regimens utilizing, in combination with progestins, substituted indoline derivative compounds which are antagonists of the progesterone receptor having the general structure: where A and B are independent substituents selected from S, CH or N; provided that when A is S, B is CH or N; and when B is S, A is CH or N; and A and B cannot both be CH; and when A and B both equal N, one N may be optionally substituted with an C 1 to C 6 alkyl group; R 1 and R 2 are independent substituents selected from the group of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , or NR B COR A ; or R 1 and R 2 are fused to form optionally substituted 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic ring, the heterocyclic ring containing one to three heteroatoms selected from the group of O, S and N; or pharmaceutically useful salts thereof. These methods of treatment may be used for contraception.

What is claimed is:  
     
       1. A method of contraception which comprises administering to a female of child bearing age for 28 consecutive days: 
       a) a first phase of from 14 to 24 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 100 μg levonorgestrel;  
       b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of an antiprogestin compound of Formula 1:                    
        wherein:  
       A and B are independent substituents selected from the group consisting of S, CH and N;  
        wherein:  
       i) when A is S, B is CH or N;  
       ii) when B is S, A is CH or N;  
       iii) A and B cannot both be CH; and  
       iv) when A and B both equal N, one N may be optionally substituted with an C 1  to C 6  alkyl group;  
       R 1  and R 2  are independent substituents selected from the group consisting of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 2  to C 6  alkenyl, substituted C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, substituted C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR B COR A ;  
       or R 1  and R 2  are fused to form:  
       v) an optionally substituted carbon-based, saturated 3 to 8 membered spirocyclic ring;  
       vi) an optionally substituted carbon-based 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds; or  
       vii) an optionally substituted 3 to 8 membered spirocyclic, heterocyclic ring containing in the backbone one to three heteroatoms selected from the group consisting of O, S and N;  
       R A  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R B  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;  
       R 3  is H, OH, NH 2 , C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 6  alkenyl, substituted C 1  to C 6  alkenyl, alkynyl, substituted alkynyl, or COR C ;  
       R C  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R 4  is viii) or ix):  
       viii) a substituted benzene ring containing the substituents X, Y and Z as shown below,                    
       X is selected from the group consisting of halogen, CN, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  thioalkyl, substituted C 1  to C 3  thioalkyl, C 1  to C 3  aminoalkyl, substituted C 1  to C 3  aminoalkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR E COR D ;  
       R D  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R E  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;  
       Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 3  alkyl, and C 1  to C 3  thioalkyl;  
       ix) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2  and NR 5 , the five or six membered ring being optionally substituted by one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkyl, C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, COR F , and NR G COR F ;  
       R F  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R G  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;  
       R 5  is H or C 1  to C 3  alkyl;  
       W is O or a chemical bond;  
       or a pharmaceutically acceptable salt thereof; and 
       c) optionally, a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no antiprogestin, progestin or estrogen is administered; wherein the total daily dosage units of the first, second and third phases equals 28.  
     
     
       2. The method according to  claim 1  wherein the progestational agent is levonorgestrel and wherein: 
       R 4  is the substituted benzene ring viii) containing the substituents X, Y and Z as shown below:                    
       X is selected from the group consisting of halogen, CN, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  thioalkyl, substituted C 1  to C 3  thioalkyl, C 1  to C 3  aminoalkyl, substituted C 1  to C 3  aminoalkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5-membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR E COR D ; or  
       R 4  is the five or six membered ring ix), wherein the five or six membered ring is optionally substituted by one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkyl, and C 1  to C 3  alkoxy.  
     
     
       3. The method according to  claim 1  wherein the progestational agent is levonorgestrel and wherein: 
       R 1 ═R 2  and are selected from the group consisting of C 1  to C 3  alkyl and substituted C 1  to C 3  alkyl, or R 1  and R 2  are fused to form a carbon-based, saturated 3 to 6 membered spirocyclic ring;  
       R 3  is H, OH, NH 2 , C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, or COR C ;  
       R C  is H, C 1  to C 3  alkyl, or C 1  to C 3  alkoxy;  
       R 4  is (x), (xi), or (xii):  
       (x) the benzene ring viii) of the structure shown below:                    
       X is selected from the group consisting of halogen, CN, C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, and C 1  to C 3  thioalkyl;  
       Y is on the 4′ or 5′ position and is selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 3  alkyl, and C 1  to C 3  thioalkyl;  
       (xi) the five membered ring ix) of the structure shown below:                    
       U is O, S, or NR 5 ;  
       X′ is selected from the group consisting of halogen, CN, NO 2 , C 1  to C 3  alkyl and C 1  to C 3  alkoxy;  
       Y′ is H or C 1  to C 3  alkyl; or  
       (xii) the six membered ring ix) having the structure:                    
       X 1  is N or CX 2 ,  
       X 2  is halogen, CN or NO 2 .  
     
     
       4. The method according to  claim 1  wherein the progestational agent is levonorgestrel and wherein: 
       R 1 ═R 2  and are selected from the group consisting of C 1  to C 3  alkyl and substituted C 1  to C 3  alkyl, or R 1  and R 2  are fused to form a carbon-based saturated 3 to 6 membered spirocyclic ring.  
     
     
       5. The method according to  claim 1  wherein the progestational agent is levonorgestrel and wherein: 
       R 1  and R 2  are fused to form a 3 to 6 membered spirocyclic ring.  
     
     
       6. A method of contraception which comprises administering to a female of child bearing age for 28 consecutive days: 
       a) a first phase of from 14 to 24 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 100 μg levonorgestrel;  
       b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of an antiprogestin compound of the formula:                    
        wherein:  
       R 1  and R 2  are independent substituents selected from the group consisting of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 2  to C 6  alkenyl, substituted C 2  to C 6  alkynyl C 2  to C 6  alkynyl, substituted C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR B COR A ;  
       or R 1  and R 2  are fused to form:  
       i) a carbon-based saturated 3 to 6 membered spirocyclic ring; or  
       ii) a carbon-based 3 to 6 membered spirocyclic ring having one or more carbon-carbon double bonds;  
       R 3  is H, OH, NH 2 , C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 6  alkenyl, substituted C 1  to C 6  alkenyl, alkynyl, substituted alkynyl, or COR C ;  
       R A  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R B  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;  
       R C  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R 4  is a substituted benzene ring containing the substituents X, Y and Z as shown below,                    
       X is selected from the group consisting of halogen, CN, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  thioalkyl, substituted C 1  to C 3  thioalkyl, C 1  to C 3  aminoalkyl, substituted C 1  to C 3  aminoalkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR E COR D ;  
       R D  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R E  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl; and  
       Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 3  alkyl, and C 1  to C 3  thioalkyl;  
       or a pharmaceutically acceptable salt thereof; and  
       c) optionally, a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no antiprogestin, progestin or estrogen is administered; wherein the total daily dosage units of the first, second and third phases equals 28.  
     
     
       7. The method according to  claim 1  in which the antiprogestin compound is 6-(3-chlorophenyl)-1,4-dihydro-4,4-dimethyl-2H-thieno[2,3-d][1,3]oxazine-2-one, or a pharmaceutically acceptable salt thereof. 
     
     
       8. The method according to  claim 1  wherein the progestational agent is selected from the group consisting of levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol, and (17-deacetyl)norgestimate. 
     
     
       9. The method according to  claim 1  which comprises administering to a female of child bearing age consecutively over a 28 day cycle: 
       a) a first phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 100 μg levonorgestrel;  
       b) a second phase of 3 daily dosage units of an said antiprogestin compound, each daily dosage unit containing said antiprogestin compound at a daily dosage of from about 2 to 50 mg; and  
       c) optionally, 4 daily dosage units of an orally and pharmaceutically acceptable placebo to be administered on each day of the 28-day cycle following the first phase and second phase.  
     
     
       10. The method according to  claim 1  in which the antiprogestin compound is 6-(3-chlorophenyl)-1,4-dihydro-4,4-dimethyl-2H-thieno[3,2-d][1,3]oxazine-2-one, or a pharmaceutically acceptable salt thereof. 
     
     
       11. A method of contraception which comprises administering to a female of child bearing age for 28 consecutive days: 
       a) a first phase of from 14 to 24 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 100 μg levonorgestrel;  
       b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of an antiprogestin compound of the formula:                    
        wherein:  
       R 1  and R 2  are independent substituents selected from the group consisting of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 2  to C 6  alkenyl, substituted C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, substituted C 2  to C 6  alkynyl, C 3  to C8 cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR B COR A ;  
       or R 1  and R 2  are fused to form:  
       i) a carbon-based saturated 3 to 6 membered spirocyclic ring; or  
       ii) a carbon-based 3 to 6 membered spirocyclic ring having one or more carbon-carbon double bonds;  
       R 3  is H, OH, NH 2 , C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 6  alkenyl, substituted C 1  to C 6  alkenyl, alkynyl, substituted alkynyl, or COR C ;  
       R A  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R B  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;  
       R C  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R 4  is a substituted benzene ring containing the substituents X, Y and Z as shown below,                    
       X is selected from the group consisting of halogen, CN, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  thioalkyl, substituted C 1  to C 3  thioalkyl, C 1  to C 3  aminoalkyl, substituted C 1  to C 3  aminoalkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR E COR D ;  
       R D  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R E  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl; and  
       Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 3  alkyl, and C 1  to C 3  thioalkyl;  
       or a pharmaceutically acceptable salt thereof; and  
       c) optionally, a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no antiprogestin, progestin or estrogen is administered; wherein the total daily dosage units of the first, second and third phases equals 28.  
     
     
       12. A method of contraception which comprises administering to a female of child bearing age for 28 consecutive days: 
       a) a first phase of from 14 to 24 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 100 μg levonorgestrel;  
       b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of an antiprogestin compound of Formula 1:                    
        wherein:  
       A and B are independent substituents selected from the group consisting of S, CH and N;  
        wherein:  
       i) when A is S, B is CH or N;  
       ii) when B is S, A is CH or N;  
       iii) A and B cannot both be CH; and  
       iv) when A and B both equal N, one N may be optionally substituted with a C 1  to C 6  alkyl group;  
       R 1  is selected from the group consisting of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR 8 COR A    
       R 2  is selected from the group consisting of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 2  to C 6  alkenyl, substituted C 2  to C 6  alkenyl, C 2  to C 6  alkyl, substituted C 2  to C 6  alkylaryl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR B COR A ;  
       or R 1  and R 2  are fused to form:  
       v) an optionally substituted carbon-based, saturated 3 to 8 membered spirocyclic ring;  
       vi) an optionally substituted carbon-based 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds; or  
       vii) an optionally substituted 3 to 8 membered spirocyclic, heterocyclic ring containing in the backbone one to three heteroatoms selected from the group consisting of O, S and N;  
       R A  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R B  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;  
       R 3  is H, OH, NH 2 , C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 6  alkenyl, substituted C 1  to C 6  alkenyl, alkynyl, substituted alkynyl, or COR C ;  
       R C  is H, C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, aryl, substituted aryl, C 1  to C 4  alkoxy, substituted C 1  to C 4  alkoxy, C 1  to C 4  aminoalkyl, or substituted C 1  to C 4  aminoalkyl;  
       R 4  is vii) or ix):  
       viii) a substituted benzene ring containing the substituents X, Y and Z as shown below:                    
       X is selected from the group consisting of halogen, CN, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  thioalkyl, substituted C 1  to C 3  thioalkyl, C 1  to C 3  aminoalkyl, substituted C 1  to C 3  aminoalkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5-membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR E COR D ;  
       R D  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
       R E  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;  
       Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 3  alkyl, and C 1  to C 3  thioalkyl; or  
       ix) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2  and NR 5 , the five or six membered ring being substituted by one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkyl, C 1  to C 3  alkoxy;  
       R 5  is H or C 1  to C 3  alkyl;  
       W is O or a chemical bond;  
       or a pharmaceutically acceptable salt thereof; and  
       c) optionally a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no antiprogestin, progestin or estrogen is administered; wherein the total daily dosage units of the first, second and third phases equals 28.  
     
     
       13. A method of contraception which comprises administering to a female of child bearing age for 28 consecutive days: 
       a) a first phase of from 14 to 24 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 100 μg levonorgestrel;  
       b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of an antiprogestin compound of Formula 1:                    
        wherein:  
       A and B are independent substituents selected from the group consisting of S, CH and N; and  
       i) when A is S, B is CH or N;  
       ii) when B is S, A is CH or N; and  
       iii) A and B cannot both be CH;  
       R 1  and R 2  are the same and are selected from the group consisting of C 1  to C 3  alkyl and substituted C 1  to C 3  alkyl, or R 1  and R 2  are fused to form a carbon-based, saturated 3 to 6 membered spirocyclic ring;  
       R 3  is H, OH, NH 2 , C 1  to C 6  alkyl, substituted C 1  to C 6  akyl, or COR C ;  
       R C  is H, C 1  to C 4  alkyl, or C 1 to C 4  alkoxy;  
       R 4  is (iv), (v) or (vi):  
       (iv) a substituted benzene ring of the structure shown below:                    
       X is selected from the group consisting of halogen, CN, C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, and C 1  to C 3  thioalkyl;  
       Y is on the 4′ or 5′ position and is selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 4  alkyl, and C 1  to C 3  thioalkyl; or  
       (v) a five membered ring of the structure shown below:                    
       U is O, S, or NR 5 ;  
       R 5  is selected from the group consisting of H, C 1  to C 3  alkyl, and C 1  to C 4  CO 2  alkyl;  
       X′ is selected from the group consisting of halogen, CN, NO 2 , C 1  to C 3  alkyl and C 1  to C 3  alkoxy;  
       Y′ is H or C 1  to C 4  alkyl; or  
       (iv) a six-membered ring with the structure:                    
       wherein X 1  is N or CX 2 , and X 2  is halogen, CN or NO 2 ;  
       and W is O or a chemical bond;  
       or a pharmaceutically acceptable salt thereof and  
       c) optionally, a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no anprogestin, progestin or estrogen is administered; wherein the total daily dosage units of the first, second and third phases equals 28.